Anti-cancer compounds / Antineoplastic Agents, chapter 38 Neoplasm: New and diseased form of tissue...
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Transcript of Anti-cancer compounds / Antineoplastic Agents, chapter 38 Neoplasm: New and diseased form of tissue...
Anti-cancer compounds / Antineoplastic Agents, chapter 38
Neoplasm: New and diseased form of tissue growth Benign (godartet) neoplasm: Easy to separate from surounding tissue,
no metastases
Malign (ondartet) neoplasm: Invassive to surounding tissue Metastases Cancer
Metastase: Secondary tumors, different location Malign cells separated from primary tumor
and spread by vascular- or lymph systh.
Terminology differents types of cancer confusing
Cell cycle: Proliferating cells
G1: Newly born cell Short period proliferating cells
S: Replication of DNAG2:M: Mitosis
G0: Non-proliferating cellQuiesence
Cell death
Control by growth factors
Control by growth factorsTumor
Inner part:Youngest cellsHypoxic regionNon-proliferating cells
Outer partProliferating cells
Most drugs act on cells in mitosis
DNA and DNA replicationDNA bases
Double -helix
Base pairs
HN
N
O
O
Thymin
N
N
NH2
O
Cytosin Adenine
N
N N
N
NH2
Guanine
HN
N N
N
O
H2N
DNA helicases: UnwindingDNA binding proteins: Prevents winding backDNA primase: formation of DNA/RNA primer (from free nucleosides in cell)DNA polymerase: Catalyse elongation of new strand (5’ - 3’)
Lagging strand:DNA ligase: Connects Okasaki fragments
Biochemical Basis of Cancer
•Mutation•Chemicals•Oncogenic Viruses•Altered Gene Expression
Mutation1. Mutation(s) = initiation (not cancer alone)2. Promotion; proliferation of mutated cells, exposure to chemical
(not carciogenic alone, ex estrogen)
Chemicals
Compounds (or metabolites) that reacts with DNA (alkylation agents)or initiate free radical processes that eventually damage DNA (Ex ionizing radiation)
Benzo[a]pyrene OH
HO
O
Metabolite
HN
N N
N
R
O
H2N
Guanine in DNA
HN
N N
N
R
O
HN
OHHO
HO
Biochemical Basis of Cancer
•Mutation•Chemicals•Oncogenic Viruses•Altered Gene Expression
Oncogenic VirusesViral DNA (or proviral RNA from RNA viruses) inserted in host DNA .... Mutation
Altered Gene ExpressionIncorrect expression of proto-oncogene
Increased express. oncogene - Increased prod. of growth factorsDecreased expression of tumor-supressor genes (anti-oncogenes)
Cancer Therapy
•Surgery
•Radiation
•Immunologican Therapy (interferons - Incr. prod. T-cells and B cells)
•Chemotherapy
•Alkylation Agents
•Antimetabolites / Nucleoside Analogs
•Antibiotics
•Antimitotic Agents
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
Alkylating Agents
HN
N N
N
R
O
H2N
Guanine in DNA
R-X HN
N N
N
R
O
H2N
R
HN
N N
N
R
O
H2N
R
HN
N N
N
R
O
H2N
R
DNA Bases - Nucleophilic Centra
HN
N
O
O
Thymin
N
N
NH2
O
Cytosin Adenine
N
N N
N
NH2
Guanine
HN
N N
N
O
H2N
HN
N N
N
NMeO
Me
Br
-218.6
-214.9HN
N N
N
NMeO
Me-225.9
-136.5138140
HN
N N
N
R
O
H2N
Guanine in DNA
HN
N N
N
R
O
H2N
X X
NH
NN
N
R
O
NH2
Also O in phosphate may be alkylated
Other 7.9-Dialkylpurinium compds
N
N N
N
NH2
Me
H
(+)-Agelasine DCl
N
N N
N
CH3O CH3
NR
R'
Heteromine A: R = R' = CH3Heteromine B: R = CH3, = R' = HHeteromine C: R = R' = H
Cl
CH3
N
N N
N
O CH3
H2N
1-Methyl-herbipoline
CH3
ClH3C
N
N N
N
O CH3
H2N
Herbipoline
CH3
Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes
ClS
Cl
Sulfur mustardMustard gassYpriteWorls war I (1917)Impurity smell like mustard / garlic
ClS
NuH
ClS
Nu
+ HCl
NuHNu
SNu
+ HCl
Br
BrRSH
Br
S
S R
Nu(i.e. DNA)
Metabolism of alkyl halidesPhase II conjug. glutathion
ClN
Cl
Me
MechlorethamineFDA 1949
N
R
HN
N
NN
R
OH2NHN
N
NN
R
O NH2
ClN
Cl
R
Rel. selective tox. to lymphoid tissue(Hodkins disease, Lymphomas)
More water sol.
Tox. to rapid proliferating cells (short time for DNA repair)
ClS
Cl ClS
NuH
ClS
Nu
+ HCl
Slow
less stable than N-aanalog
Moderate
ClN
Cl ClN
NuH
ClN
Nu
+ HCl
Fast
Moderate
R
R2- order kinetics
1. order kinetics(1. step rat lim)
R=Alkyl
R
ClN
Cl ClN
NuH
ClN
Nu
+ HCl
Slow
ModeratePh
Lone pair delocalizedLess nucleophilic
Ph1. order kinetics(1. step rat lim)
ClN
Cl
POHN
O
HNCl
PON
OCl
ClN
Cl
NH2
CO2H
ClN
Cl
CO2H
L-isomerActive transport mech (L-AA)
Aryl decrease reactivity
ChlorambucilLeukeran®,
MelfalanAlkeran®,
CyclophosphamideSendoxan®
Pro-drug
IfosfamideHoloxan®
Pro-drug
ClN
Cl
POHN
OCYP450
ClN
Cl
POHN
O
HO
≈Hemiacetal
ClN
Cl
POH2N
O
O
Not nucleophiliccf amides
H
B
O
ClN
Cl
POH2N
O
Active compound
More nucøeophilicNeg charge (phys. pH)prevents delocal.
Cl
HN
Cl
MESNA Co-admin.
ClN
Cl
POHN
O
ClN
Cl
POH2N
O
OH
B
O
ClN
Cl
POH2N
O
OS
O OSH O
Activation by CYP450 (CYP3A4); enzym indusing drugs may increase activity
CYP3A4 inhibitors
Decrease activation of cyclophosfamide
O
O
O O
Flavenoid / coumarine dersee p 225
Estramustine phosphateEstracyt®
Pro-drug
O
O P
O
O
O
Na
Na
N
O
Cl
Cl
Water solubility
1) Oral absorb2) Fast metabol.
O
OH
N
O
Cl
Cl
Main comp. plasma
EstradiolCarry to cells with estrogenic receptors
Estrogenic (Anti-androgenic) effect protate cancerCleaved to active alkylating agent?
Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes
Busulfan
SO
OS
O O
O O
Not reg. NMono or dialkylationBetter leav. gr, not 3-embered ring intermedcf dimethyl sulfate
Thiotepa
P
S
N N
N
Nu
Even more reactive at low pH
P
S
N N
N
H
Not reg. N
TemozolomideTemodal®
N
NN
N
N
O
NH2
O
Hydrolysis NHHN
N
N
N
CH3
NH2
O
NH
NH2
NNH2
O
N
N
H H
N
N
H H
LomustineLomustine medac® Nitrosoureas
O
NH
NR'R
NO
O
NH
N
NO
ClWeak base
O
N N
NO
ClO
NN N O
H
NC
O
+N
N
OH
N2 OH
Reactive vinilic cation
DNA-Nu
isocyanate
H20
NH2
CO2
Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes
PtH3N NH3
XX
cis
PtX NH3
XH3N
trans
Square planar Pt-complexes; Pt(II)
Pt2+
10 electrons
X
NH3NH3
X
18 electron Pt-complex
c.f. (Ph3P)2PdCl2
PtH3N NH3
XX
cis
2 DNA-Nu
PtH3N NH3
Nu-DNADNA-Nu
(Complexes with trans isomers are more readily regognized and repaired)
+ 2 Cl
NH3
PtH3N Cl
ClIntracellLow Cl-conc
H2O NH3
PtH3N OH2
Cl
+NH3
PtH3N OH2
OH2
2+
Pt(II) [as Pd(II)] electrophilicNucleophilic subst.
OPt
OPt
H H
H H
NH3
NH3
H3N
H3N
2+
Most probably
Guanine
Guanine
Guanine
Guanine PtNH3
NH3
Preferably: Binding to N7 in guanine 1,2-Intrastrand
NH3
PtH3N N
N
N
NR
HNN
O
H2N
N
HN NH2O
Guanine
Guanine PtNH3
NH3
Certain proteins binds to bent DNA, and prevents normal repair
Pt replace Zn in necessary transcription factors
DNA polymerase “collides” with Pt, DNA strain breaks mechanically
NH3
PtH3N Cl
Cl
NH3
PtH3N O
O
O
O
CisplatinPlatinol® Platistin®
CarboplatinCarboplatin® Carbosin® Paraplatin®More stabile comp. (reacts less readily with water)